Device for the formation and delivery of a mixture, notably for the surgical application of this mixture.
The present invention concerns a device for the formation and application of a mixture of two constituents, notably, the delivery of a mixture for surgical application, such as, in particular, a collagen preparation.
Collagen preparations, designed for application in fluid form, as a liquid or paste, for example, have already been proposed for surgical application, notably in the form of surgical adhesive.
Application WO 97/29715 concerned the proposal of adhesives made from a mixture of gelatine and a polyaldehyde type of crosslinking agent, to produce a fluid mixture for application at a relatively high temperature, above 50xc2x0 C. Such temperatures are much too high for some tissues, notably in central nervous system surgery, fine innervated, vascularized tissues such as vascular and digestive walls, particularly the blood vessels, heart, intestines and uterus. It should be emphasized that official standards require a temperature lower than 41xc2x0 C. for the product applied.
Collagen preparations are also known in the form of adhesive described in application WO 98/15299, applied in the form of a mixture of a collagenic substance and a polyaldehyde agent, for example, starch. This mixture can be applied in fluid form at a temperature of around 37xc2x0 C., which is optimal. This type of mixture is characterized particularly by a substance of collagenic origin as defined in the afore-mentioned application, for example, a collagen which has lost at least part of its spiral, non hydrolyzed structure, consisting mainly of alpha chains.
For these preparations, to make an extemporaneous mixture easily, i.e. prepared at the time the surgeon is ready to apply the preparation consisting of a collagenic substance and a crosslinking agent, it is favourable to raise the collagenic preparation to a temperature higher than the application temperature, for example to a temperature of around 42xc2x0 C. to 50xc2x0 C., necessary to achieve adequate fluidity. The problem is then to administer the mixture to the receiving tissue at a temperature close to body temperature at 37xc2x0 C., or in any case, lower than 41xc2x0 C.
It has already been proposed to make these mixtures at the last moment, having previously raised the temperature of the preparation of collagenic substance in a drying oven or a water bath. This method of preparation has a number of disadvantages, however, for use under hospital conditions, notably because the heated product begins to cool as soon as it leaves the thermostatically controlled atmosphere, so that the temperature of the product applied is not constant and is difficult to control.
The invention therefore proposes to provide a device which can be used to prepare an extemporaneous mixture, at the time of application by the surgeon, of a collagenic substance and a crosslinking agent, for delivery of a mixture at a temperature close to body temperature.
It should be noted that this objective is made particularly difficult in that collagen or gelatine solutions are extremely viscous, whereas solutions of crosslinking agents display very low viscosity and it is difficult to mix fluids of very different viscosities.
Another of the invention""s objectives is to provide such a device which displays a high level of safety with respect to delivery at the required temperature.
Another of the invention""s objectives is to provide such a device which can be used to provide several deliveries separated by time intervals likely to cause considerable polymerization of the mixture.
Another of the invention""s objectives is to provide such a device which is extremely practical to use.
Another objective is to provide such a device which can be used to deliver the mixture in the form of a foam.
The invention""s objective is to provide a device for the formation and delivery of a mixture, notably for the surgical application of this mixture, characterized in that it includes:
a receptacle suitably shaped for handling by the surgeon and including means of holding two syringe barrels, these being a syringe containing the first constituent of the mixture, for example, a collagenic solution, and a syringe containing the second constituent of the mixture, for example, a solution of crosslinking agent;
means for simultaneously expelling the contents of the two syringes;
the means of maintaining the contents of the syringe holding the first constituent, for example, the collagenic solution, at a fixed temperature in excess of body temperature, for example, about 45xc2x0 C. to 50xc2x0 C.
and a mixer receiving the contents of both syringes simultaneously during application, which mixing device also secures cooling.
The means of heating the contents of the syringe favourably includes an electrical resistance or thermistor. This resistance can be fitted to the receptacle itself.
It is preferable, however, that this electrical resistance should be permanently fastened to the barrel of the syringe, for example, in the form of a resistance embedded in a film glued around the body of the syringe. The electrical power supply for this film can be provided, for example, by conductors connected to the film and terminating in a means of connection to a source of electrical power, either directly from an appropriate battery, or by using a complementary means of connection which is then connected to the source of electrical power. In this last case, when the device is in use, the user must also connect the conductors leading from the barrel of the syringe to the complementary means of connection.
A thermostat can be used favourably, preferably also fixed to the barrel of the syringe, to control the power supply to the thermistor and detect when the required temperature is reached. This thermostat then preferably emits a signal, informing the surgeon that the syringe has reached the desired temperature. Setting and fitting such a thermostat are routine operations for technicians.
Preferably, an extra safety thermostat is provided in the circuit, this thermostat being designed to cut the thermistor""s power supply when a temperature safety threshold is reached or exceeded, this thermostat, in addition, only restoring the power supply once the temperature has fallen back to a level which is substantially below the predetermined temperature setting, so that the first thermostat cannot emit a signal before a new correct heating cycle has been completed.
The mixer will preferably include a removable connector used to receive the contents of the two syringes and carry them to the inlet of an end-piece or mixer body extension containing a device fitted with baffles providing obstacles which gradually produce a homogeneous mixture.
This mixer body will preferably include extended particles and it is particularly preferred that these particles be formed of small sections of plastic tubing or other cut in two across the diameter. It was observed that this type of structure ensures intermingling of the particles leading to obtention of the mixture required, over a short distance of a few centimetres, while ensuring that the temperature falls during its passage through the mixer, which constitutes one of the invention""s characteristics.
The connector and mixer end-piece can preferably be removed separately and are replaceable, which means that the contents of the syringes can be used in several successive applications, separated by long periods in spite of the start of polymerization of the mixture in the end-piece or body of the mixer which will simply be replaced.
In the preferred application of the invention, using a collagen constituent or gelatine, as defined, for example in WO 98/15299, the volume of the expellable contents of the syringe containing the first constituent, i.e. the collagenic constituent, is about three to ten times as much, for example four times as much as that of the contents of the second syringe, i.e. the solution of crosslinking agent, such as a solution of oxidized starch.
When the collagenic constituent of the first syringe is in the form of a homogeneous liquid solution, this ratio is preferably between 3 and 6. When the collagenic constituent of the first syringe is in the form of a liquid foam containing air in emulsion in an aqueous solution, this ratio must be increased to 6 to 10. Indeed, the second syringe must be smaller to take into account the reduced volume of aqueous solution in the first syringe.
Preferably, the conduit from the connector which is connected to the first syringe, is subdivided into several channels so that several equidistant feeds are produced leading into the mixer end-piece or body, while the conduit connected to the second syringe forms only a single central channel.
Thus, for example, the single channel is positioned centrally in the connector and the four equidistant channels connected to the first syringe are positioned concentrically around the singe channel.
The outlet of the four channels penetrates the start of the mixer end-piece where the mixture will be made homogeneously.
For application of such a collagenic mixture, it is preferable for the temperature of the contents of the first syringe, containing the original collagenic constituent, to be raised by the electrical heating system, to a constant temperature selected within the 42xc2x0 C. to 57xc2x0 C. range and: preferably between 44xc2x0 C. and 50xc2x0 C., the other constituent, i.e. the crosslinking agent being at ambient temperature, generally the temperature of the operating theatre; the length of the mixer end-piece is then preferably around 2 to 4 cm and it is observed that it is possible to obtain an extremely homogeneous mixture at the outlet, at a temperature of around 37xc2x0 C., and below 41xc2x0 C.; or preferably between 48xc2x0 C. and 54xc2x0 C., the other constituent being at ambient temperature, the length of the mixer end-piece being 2 to 4 cm and extended by a laparoscopy tube, preferably around 25 to 35 cm long.
The mixture which is delivered by this device according to the invention, can be a mixture which is delivered in the form of a liquid or a fluid gel, or in the form of a foam resulting from an emulsion using a preferably sterile gaseous constituent, for example, air.
The foam can be formed in situ in the mixer by discharging a source of gas into the mixer, for example at the inlet or during its passage through the mixer. This source of gas can be a third syringe containing the gas, the content of which is expelled at the same time as that of the other two syringes to pass through the mixer simultaneously.
Still considering the case of a mixture in the form of foam, the first constituent of the mixture can itself be a foam, which may either be formed in the barrel of the first syringe or introduced into this barrel, transported, if necessary, and maintained in this barrel at the predetermined temperature setting, which also keeps the foam stable.
The first foam constituent can be prepared either in the barrel of the syringe or outside it, for example in another syringe connected to the first one, by mixing the gas to the liquid constituent. As a variant, the foam can be prepared favourably by mixing a dry powder, consisting of the protein components of the first constituent, and a gas, for example, air, with the solvent, for example, physiological saline. Very favourably, the gas used can be the one which is naturally contained or incorporated in the empty volume of a powder form of the protein element in proportion to the swelling ratio of this powder, the solvent then being added to this biphasic solid-gas mixture.
These various variants of the formation of the first foam constituent can appropriately use the barrel of the first syringe, i.e. the syringe which is likely to be heated, and another syringe, each one containing one or more components of the constituent, which, when they are mixed, form the foam, preferably by successive repeated transfers from one syringe to the other, the foam formed being finally contained in the first syringe fitted with the heating means.
As a variant, instead of an extra syringe, the heating syringe can be connected to a flask of appropriate volume, such that injecting the contents of the syringe into the flask causes excess pressure which pushes the contents into the syringe when the plunger is released.
The invention also concerns a set, or kit consisting of a receptacle, as defined in the present invention, a first syringe barrel containing a first constituent, sealed by a stopper, a second syringe barrel containing the second constituent, sealed by a stopper, and a mixer end-piece containing the intermingled particles.
The first constituent is preferably a collagen solution as defined in application WO 98/15299, or an aqueous collagen foam in an emulsion with a gas, for example, air, and the second constituent is a polyaldehyde solution, notably oxidized starch.
The invention also concerns the processes used to prepare the liquid or foam-based mixtures described above.
The invention also concerns a syringe fitted with the means for maintaining its contents at a predetermined temperature setting, for example, close to body temperature, or higher, for example, around 45xc2x0 C. to 50xc2x0 C.
This syringe can be used in the device or kit described above, but it can also be used individually, its content being used in any other application.
Among these applications, one consists of heating the syringe containing a viscous product to reduce the viscosity and facilitate administration, for example, hyaluronic acid or gelatine or collagen, for example, for intra-ocular administration.
In another application it is used to heat a previously frozen product to accelerate and facilitate its use.
The means described above can be used to advantage as the means of maintaining the temperature.